Highly Active Antiretroviral Therapy (HAART) regimens containing protease inhibitors (PIs) and/or reverse transcriptase inhibitors (RTIs) cause profound and sustained suppression of HIV replication reduce morbidity and mortality and slow disease progression. However, the development of resistance to these drugs has limited the benefit of such treatments and their widespread use may result in increased transmission of drug-resistant HIVstrains. Transmission of virus resistant to both RTIs and PIs has been documented to occur via all major routes: perinatal, transfusion, sexual, and parenteral. Two recent cross-sectional studies have estimated the transmission of resistance to be as high as 16% by genotypic assays and 26% by phentoypic assays. However, only 3% of the study populations were injection drug users (IDUs). We conducted a preliminary investigation of genotypic resistance in IDUs against the 14 currently FDA-approved anti-HIV drugs. Among 20 recent IDU seroconverters, we observed that more than half were infected with HIV containing at least one mutation at a codon associated with drug resistance. Given this preliminary data, we are proposing to investigate the transmission of drug-resistant HIV strains and examine their persistence after seroconversion. These aims will be achieved by using already collected data and samples from our ongoing prospective cohort study based in Baltimore's population of IDUs- the AIDS Links to the Intravenous Experience (ALIVE) study. First, to estimate the level of new infection with drug-resistant HIV, we will determine the cumulative incidence of drug-resistant HIV in seroconverters from 1988 to 2003 (N=345 [305 through 1998 and 40 projected]) using both genotypic and phenotypic assays. We also have the unique opportunity to investigate the tendency for wild type virus to outgrow drug-resistant HIV strains using frozen repository specimens collected after seroconversion. Our findings will have important implications for the utility of resistance testing in treatment-naive individuals. Moreover, this study will provide critical population-based. epidemiologic data on the estimation of the transmission rate of drug-resistant HIV in the largest known cohort study of IDUs in the U.S.